The present invention relates to a novel process for preparing certain griseolic acid derivatives, which process enables the derivatives to be prepared in a high yield and by means of a simple process.
Griseolic acid is a nucleoside-type compound having an adenine base and two carboxylic acid groups. It was first disclosed in, inter alia, European Patent Specification No. 29,329A, and subsequently its structure was disclosed in U.S. Pat. No. 4,460,765.
Subsequently, copending U.S. patent application Ser. No. 664,866, filed on Oct. 25, 1984, which issued as U.S. Pat. No. 4,634,706, (and of which the present application is a continuation-in-part) disclosed a class of griseolic acid derivatives having activities at least as good as the natural product, griseolic acid, but having significantly lower toxicities. Certain of the compounds prepared by the process of the present invention are embraced by the general disclosure of said U.S. patent application, although only one such compound, N.sup.6 -methylgriseolic acid, is specifically disclosed. Other compounds prepared by the present invention are disclosed in copending U.S. patent application Ser. No. 854,418 filed Apr. 21, 1986 and entitled "Griseolic Acid Derivatives, Their Preparation and Their Use" now abandoned, and assigned to the present assignees.
The general class of griseolic acid derivatives, and especially the N.sup.6 -alkyl and N.sup.6 -aralkyl griseolic acid derivatives, are non-toxic and have a variety of valuable therapeutic activities arising primarily from their abilities to inhibit the activity of phosphodieserases (PDE) of, for example, cyclic adenosine monophosphate (cAMP). For example, they have shown the potential to be used as ameliorators of cerebral function, as angiocardiokinetic agents, as antithrombotic agents, as diuretics, as psychotropic and neurotropic agents, as smooth muscle relaxants and as anticancer agents.
However, it is always necessary that drugs should be capable of preparation at a cost at most commensurate with their therapeutic value and preferably as cheaply as possible. In any case, regardless of cost, where a drug is prepared by a multi-stage sequence of reactions or in low yield, there is always an increased danger that the drug may be contaminated by by-products which may be difficult or impossible to remove, and its value may thereby be degraded.